1. Field of the Invention
Nortriptyline is a tricyclic antidepressant which finds extensive use. The therapeutic range for the drug is from about 50 to 175 ng/ml. Lower dosages do not have significant effect and overdosages have substantial side effects which can be life-threatening. Overdoses can result in convulsions, coma, cardiac arrhythmias, and anticholinergic signs, such as mydriasis and tachycardia.
It is found that the rate of metabolism of the drug can vary widely with individuals, as well as the sensitivity of the individual to the drug. It is therefore necessary to insure proper dosage levels to monitor the plasma level, so that a therapeutic dosage level may be maintained.
In monitoring the dosage level, it is desirable that there be a simple, accurate, rapid technique for measuring the nortriptyline level, which can distinguish nortriptyline from other drugs and metabolites of nortriptyline, which might otherwise give an erroneous value of the nortriptyline level.
2. Brief Description of the Prior Art
Nortriptyline is closely related chemically to amitriptyline. Techniques reported for the determination of amitriptyline in biological fluids include the use of thin-layer chromatography, gas-liquid chromatography (GLC) and GLC-mass spectrometry. Gifford, et al., J. Chrom., 105: 107-113 (1975); Gupta, et al., Clin. Biochem., 9: 247-51 (1976); Nyberg and Martensson, J. Chromatography, 143: 491 (1977); Watson and Stewart, J. Chrom., 134: 182 (1977); ibid. 132: 155-159 (1977). Radioimmunoassay has been reported for amitriptyline by Aherne, et al., Br. J. Clin. Pharmac., 3: 561 (1976), Turner, Lancet, 1316 (1977); and Aherne, et al., Lancet 1214 (1977). In Aherne, et al., ibid., a synthesis for an antigen for antibody formation is described, where nortriptyline was substituted with aminobutylene followed by conjugation to bovine serum albumin employing carbodiimide. In another antigen conjugates synthesis by Kaul, et al., J. Anal. Tox., 1: 236 (1977), nortriptyline was conjugated to bovine serum albumin through a succinic group. The resulting antibodies were found to have significant cross-reactivity with a number of other tricyclic drugs.
U.S. Pat. No. 4,275,160 discloses imipramine derivatives and poly(amino acid) conjugates. U.S. Pat. No. 4,307,245 describes amitripylyine conjugates to antigenic proteins and enzymes. U.S. Pat. No. 4,220,722 discloses a method for conjugating to polyamino compounds employing haloacyl groups and compositions prepared thereby. U.S. Pat. No. 3,458,578 discloses 4-amino-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one. U.S. Pat. No. 3,803,234 generically discloses 2- and 3-nitro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one.